Leptin, the protein product of the obese gene, is a hormone secreted by fat cells that is integral to food intake regulation in mammals. Leptin signals to the brain information about long term energy balance, and thus influences critical aspects of the life cycle such as growth and reproduction in many species. Additionally, the prevalence of obesity in developed countries in recent years has focused intense interest on leptin and other factors that influence appetite and energy metabolism. Dr. Denver's lab reported the first definitive identification of the obese gene and the functional characterization of leptin in a nonmammalian species, the South African clawed frog, Xenopus laevis. Until now, virtually nothing was known about the biology of leptin outside of mammals. The overall goal of this research is to understand the functions of leptin in a cold blooded species, Xenopus laevis, whose lineage diverged from that of modern mammals over 200 million years ago. The frog has been, and continues to be an important model organism for the study of animal development. Using molecular, physiological and developmental approaches, the major questions to be addressed in this research are: 1) Does leptin play an evolutionarily conserved role in long term energy balance in frogs, and thereby influence critical aspects of the amphibian life history such as metamorphosis, growth and reproduction? 2) Where and when in the frog's body is leptin produced, and where are leptin's major sites of action? 3) Does leptin influence tadpole brain development, alter tadpole growth and the timing of metamorphosis? This project, which will offer unique training opportunities for undergraduate and graduate students, will provide a foundation for understanding the functional evolution of this important vertebrate hormone, and establish the frog as a model system for the study of leptin actions in early development. Basic research on the hormonal control of appetite and feeding is particularly timely given the global concern over the rising incidence of obesity and related disorders in humans.
Leptin, the protein product of the obese gene, is a hormone secreted by fat cells that is integral to food intake regulation in mammals. Leptin acts on the brain to signal when the body has sufficient energy stores, thus inhibiting appetite (it functions as an ‘adipostat’). Mutations in the obese gene cause obesity in mice and humans. Since its discovery scientists have attempted to isolate orthologous genes from nonmammalian vertebrates with limited success. We reported the first definitive identification of the obese gene and its receptor (the LepR), and the functional characterization of leptin in a nonmammalian species, the frog Xenopus. Our research showed that this important signaling molecule was present in the earliest land dwelling vertebrates and its functions have been largely conserved through evolution. We isolated the full-length frog LepR and showed that frog leptin signals through evolutionarily conserved intracellular pathways. However, we also discovered that the cytoplasmic domain of the frog LepR, like the human but unlike the mouse, has additional tyrosine amino acid residues that may engage novel signaling pathways. We investigated the ontogeny of leptin signaling in the tadpole, and defined the stage of postembryonic development at which time the anorexigenic actions of leptin develop. We provided evidence that leptin action is responsible for the cessation of feeding that occurs at the time of metamorphosis when the gut undergoes extensive remodeling. Furthermore, our work has extended the known roles of leptin in vertebrates to several important actions during early postembryonic development. For example, we discovered that leptin and its receptor are widely expressed in the tadpole and frog, supporting that the hormone has functions beyond its role as an 'adipostat'. We showed that leptin functions as an early developmental signal to induce cell proliferation in the brain, possibly acting via the Wnt/beta-catenin signaling pathway. Our research has shown that leptin is an ancient hormone that plays critical roles in vertebrate development and physiology, and establishes the frog Xenopus as an important model organism for leptin biology. Broader Impacts: The topic of this research is timely given global concern over the rising incidence of obesity and associated disorders in humans. Recent findings show that early life nutrition, both excess and malnutrition, can have profound effects on later life health and disease in humans and wild animals. The hormone leptin, acting during early development, may play a role in these effects that persist into adulthood, and our basic research has helped define the pathways through which the hormone can exert developmental actions. This award has provided training opportunities for a diverse group of students that included six graduate students (5 women), one woman postdoctoral scientist and ten undergraduate students (6 women, 2 African-American).
